TY - JOUR
T1 - Plasma-Soluble Biomarkers for Fibrodysplasia Ossificans Progressiva (FOP) Reflect Acute and Chronic Inflammatory States
AU - Pignolo, Robert J.
AU - McCarrick-Walmsley, Ruth
AU - Wang, Haitao
AU - Qiu, Shirley
AU - Hunter, Jeffrey
AU - Barr, Sharon
AU - He, Kevin
AU - Zhang, Hui
AU - Kaplan, Frederick S.
N1 - Funding Information:
This work was supported by a grant from Alexion Pharmaceuticals, Inc. (FSK, RJP), the Radiant Hope Foundation (RJP), the Robert and Arlene Kogod Professorship (RJP), and the Isaac & Rose Nassau Professorship of Orthopaedic Molecular Medicine (FSK).
Publisher Copyright:
© 2021 American Society for Bone and Mineral Research (ASBMR).
PY - 2022/3
Y1 - 2022/3
N2 - Fibrodysplasia ossificans progressiva (FOP) is a progressive, debilitating genetic disease in which skeletal muscle and connective tissue is episodically replaced by heterotopic bone. Discovery of surrogate biomarkers of disease (genotype)-related and flare-up-associated activity of FOP in a readily accessible matrix, such as plasma, would facilitate an understanding of the complex pathophysiology of FOP, aid patient care, and provide a valuable tool for the development and monitoring of potential therapeutics. In a case–control study, using a carefully collected and curated set of plasma samples from 40 FOP patients with the classic ACVR1R206H mutation and 40 age- and sex-matched controls, we report the identification of disease-related and flare-up-associated biomarkers of FOP using a multiplex analysis of 113 plasma-soluble analytes. Adiponectin (implicated in hypoxia, inflammation, and heterotopic ossification) as well as tenascin-C (an endogenous activator of innate immune signaling through the TLR4 pathway and a substrate for kallikrein-7) were highly correlated with FOP genotype, while kallikrein-7 was highly correlated with acute flare-up status. Plasma-soluble biomarkers for FOP support a flare-up-related acute inflammatory phase of disease activity superimposed on a genotypic background of chronic inflammation.
AB - Fibrodysplasia ossificans progressiva (FOP) is a progressive, debilitating genetic disease in which skeletal muscle and connective tissue is episodically replaced by heterotopic bone. Discovery of surrogate biomarkers of disease (genotype)-related and flare-up-associated activity of FOP in a readily accessible matrix, such as plasma, would facilitate an understanding of the complex pathophysiology of FOP, aid patient care, and provide a valuable tool for the development and monitoring of potential therapeutics. In a case–control study, using a carefully collected and curated set of plasma samples from 40 FOP patients with the classic ACVR1R206H mutation and 40 age- and sex-matched controls, we report the identification of disease-related and flare-up-associated biomarkers of FOP using a multiplex analysis of 113 plasma-soluble analytes. Adiponectin (implicated in hypoxia, inflammation, and heterotopic ossification) as well as tenascin-C (an endogenous activator of innate immune signaling through the TLR4 pathway and a substrate for kallikrein-7) were highly correlated with FOP genotype, while kallikrein-7 was highly correlated with acute flare-up status. Plasma-soluble biomarkers for FOP support a flare-up-related acute inflammatory phase of disease activity superimposed on a genotypic background of chronic inflammation.
KW - ADIPONECTIN
KW - BIOMARKERS
KW - FIBRODYSPLASIA OSSIFICANS PROGRESSIVA
KW - HETEROTOPIC OSSIFICATION
KW - KALLIKREIN-7
KW - TENASCIN-C
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U2 - 10.1002/jbmr.4492
DO - 10.1002/jbmr.4492
M3 - Article
C2 - 34954853
AN - SCOPUS:85123493730
SN - 0884-0431
VL - 37
SP - 475
EP - 483
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 3
ER -